tbuckley/cabot-search huggingface dataset:
A H3K27M-targeted vaccine in adults with diffuse midline glioma
Authors: Niklas Grassl, Isabel Poschke, Katharina Lindner, Lukas Bunse, Iris Mildenberger, Tamara Boschert, Kristine Jähne, Edward W. Green, Ingrid Hülsmeyer, Simone Jünger, Tobias Kessler, Abigail K. Suwala, Philipp Eisele, Michael O. Breckwoldt, Peter Vajkoczy, Oliver M. Grauer, Ulrich Herrlinger, Joerg-Christian Tonn, Monika Denk, Felix Sahm, Martin Bendszus, Andreas von Deimling, Frank Winkler, Wolfgang Wick, Michael Platten, Katharina Sahm
Journal: Nature Medicine (2023)

Substitution of lysine 27 to methionine in histone H3 (H3K27M) defines an aggressive subtype of diffuse glioma. Previous studies have shown that a H3K27M-specific long peptide vaccine (H3K27M-vac) induces mutation-specific immune responses that control H3K27M+ tumors in major histocompatibility complex-humanized mice. Here we describe a first-in-human treatment with H3K27M-vac of eight adult patients with progressive H3K27M+ diffuse midline glioma on a compassionate use basis. Five patients received H3K27M-vac combined with anti-PD-1 treatment based on physician's discretion. Repeat vaccinations with H3K27M-vac were safe and induced CD4+ T cell-dominated, mutation-specific immune responses in five of eight patients across multiple human leukocyte antigen types. Median progression-free survival after vaccination was 6.2 months and median overall survival was 12.8 months. One patient with a strong mutation-specific T cell response after H3K27M-vac showed pseudoprogression followed by sustained complete remission for >31 months. Our data demonstrate safety and immunogenicity of H3K27M-vac in patients with progressive H3K27M+ diffuse midline glioma.
APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer
Authors: Jennifer L. McCann, Agnese Cristini, Emily K. Law, Seo Yun Lee, Michael Tellier, Michael A. Carpenter, Chiara Beghè, Jae Jin Kim, Anthony Sanchez, Matthew C. Jarvis, Bojana Stefanovska, Nuri A. Temiz, Erik N. Bergstrom, Daniel J. Salamango, Margaret R. Brown, Shona Murphy, Ludmil B. Alexandrov, Kyle M. Miller, Natalia Gromak, Reuben S. Harris
Journal: Nature Genetics (2023)

Abstract The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer.
Functional characterization of Alzheimer’s disease genetic variants in microglia
Authors: Xiaoyu Yang, Jia Wen, Han Yang, Ian R. Jones, Xiaodong Zhu, Weifang Liu, Bingkun Li, Claire D. Clelland, Wenjie Luo, Man Ying Wong, Xingjie Ren, Xiekui Cui, Michael Song, Hongjiang Liu, Cady Chen, Nicolas Eng, Mirunalini Ravichandran, Yang Sun, David Lee, Eric Van Buren, Min-Zhi Jiang, Candace S. Y. Chan, Chun Jimmie Ye, Rushika M. Perera, Li Gan, Yun Li, Yin Shen
Journal: Nature Genetics (2023)
Discrimination of cell-intrinsic and environment-dependent effects of natural genetic variation on Kupffer cell epigenomes and transcriptomes
Authors: Hunter Bennett, Ty D. Troutman, Enchen Zhou, Nathanael J. Spann, Verena M. Link, Jason S. Seidman, Christian K. Nickl, Yohei Abe, Mashito Sakai, Martina P. Pasillas, Justin M. Marlman, Carlos Guzman, Mojgan Hosseini, Bernd Schnabl, Christopher K. Glass
Journal: Nature Immunology (2023)

Abstract Noncoding genetic variation drives phenotypic diversity, but underlying mechanisms and affected cell types are incompletely understood. Here, investigation of effects of natural genetic variation on the epigenomes and transcriptomes of Kupffer cells derived from inbred mouse strains identified strain-specific environmental factors influencing Kupffer cell phenotypes, including leptin signaling in Kupffer cells from a steatohepatitis-resistant strain. Cell-autonomous and non-cell-autonomous effects of genetic variation were resolved by analysis of F1 hybrid mice and cells engrafted into an immunodeficient host. During homeostasis, non-cell-autonomous trans effects of genetic variation dominated control of Kupffer cells, while strain-specific responses to acute lipopolysaccharide injection were dominated by actions of cis -acting effects modifying response elements for lineage-determining and signal-dependent transcription factors. These findings demonstrate that epigenetic landscapes report on trans effects of genetic variation and serve as a resource for deeper analyses into genetic control of transcription in Kupffer cells and macrophages in vitro.
Prior vaccination promotes early activation of memory T cells and enhances immune responses during SARS-CoV-2 breakthrough infection
Authors: Mark M Painter, Timothy S Johnston, Kendall A Lundgreen, Jefferson J S Santos, Juliana S Qin, Rishi R Goel, Sokratis A Apostolidis, Divij Mathew, Bria Fulmer, Justine C Williams, Michelle L McKeague, Ajinkya Pattekar, Ahmad Goode, Sean Nasta, Amy E Baxter, Josephine R Giles, Ashwin N Skelly, Laura E Felley, Maura McLaughlin, Joellen Weaver, Oliva Kuthuru, Jeanette Dougherty, Sharon Adamski, Sherea Long, Macy Kee, Cynthia Clendenin, Ricardo da Silva Antunes, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Alexander C Huang, Daniel J Rader, Scott E Hensley, Paul Bates, Allison R Greenplate, E John Wherry
Journal: Nature Immunology (2023)
Multimodal single-cell datasets characterize antigen-specific CD8+ T cells across SARS-CoV-2 vaccination and infection
Authors: Bingjie Zhang, Rabi Upadhyay, Yuhan Hao, Marie I Samanovic, Ramin S Herati, John D Blair, Jordan Axelrad, Mark J Mulligan, Dan R Littman, Rahul Satija
Journal: Nature Immunology (2023)

Abstract The immune response to SARS-CoV-2 antigen after infection or vaccination is defined by the durable production of antibodies and T cells. Population-based monitoring typically focuses on antibody titer, but there is a need for improved characterization and quantification of T cell responses. Here, we used multimodal sequencing technologies to perform a longitudinal analysis of circulating human leukocytes collected before and after immunization with the mRNA vaccine BNT162b2. Our data indicated distinct subpopulations of CD8 + T cells, which reliably appeared 28 days after prime vaccination. Using a suite of cross-modality integration tools, we defined their transcriptome, accessible chromatin landscape and immunophenotype, and we identified unique biomarkers within each modality. We further showed that this vaccine-induced population was SARS-CoV-2 antigen-specific and capable of rapid clonal expansion. Moreover, we identified these CD8 + T cell populations in scRNA-seq datasets from COVID-19 patients and found that their relative frequency and differentiation outcomes were predictive of subsequent clinical outcomes.
The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Authors: Shun-Fat Lau, Wei Wu, Hiu Yi Wong, Li Ouyang, Yi Qiao, Jiahui Xu, Jessica Hiu-Yan Lau, Carlton Wong, Yuanbing Jiang, David M. Holtzman, Amy K. Y. Fu, Nancy Y. Ip
Journal: Nature Aging (2023)

Abstract In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.
Multiplexed discrimination of SARS-CoV-2 variants via plasmonic-enhanced fluorescence in a portable and automated device
Authors: Ying Liu, Yang Yang, Guanghui Wang, Dou Wang, Pan-Lin Shao, Jiahu Tang, Tingzhen He, Jintao Zheng, Ruibin Hu, Yiyi Liu, Ziyi Xu, Dan Niu, Jiahui Lv, Jingkai Yang, Hongjun Xiao, Shuai Wu, Shuang He, Zhongrong Tang, Yan Liu, Meijie Tang, Xingyu Jiang, Jing Yuan, Hongjie Dai, Bo Zhang
Journal: Nature Biomedical Engineering (2023)
Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice
Authors: Zhenyu Yao, Ying Gong, Wenbin Chen, Shanshan Shao, Yongfeng Song, Honglin Guo, Qihang Li, Sijin Liu, Ximing Wang, Zhenhai Zhang, Qian Wang, Yunyun Xu, Yingjie Wu, Qiang Wan, Xinya Zhao, Qiuhui Xuan, Dawei Wang, Xiaoyan Lin, Jiawen Xu, Jun Liu, Christopher G. Proud, Xuemin Wang, Rui Yang, Lili Fu, Shaona Niu, Junjie Kong, Ling Gao, Tao Bo, Jiajun Zhao
Journal: Nature Metabolism (2023)

Abstract Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.
A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer
Authors: Sara Bobisse, Valentina Bianchi, Janos L Tanyi, Apostolos Sarivalasis, Edoardo Missiaglia, Rémy Pétremand, Fabrizio Benedetti, Drew A Torigian, Raphael Genolet, David Barras, Alexandra Michel, Spyridon A Mastroyannis, Emese Zsiros, Denarda Dangaj Laniti, Zoi Tsourti, Brian J Stevenson, Christian Iseli, Bruce L Levine, Daniel E Speiser, David Gfeller, Michal Bassani-Sternberg, Daniel J Powell, Carl H June, Urania Dafni, Lana E Kandalaft, Alexandre Harari, George Coukos
Journal: Nature Cancer (2023)
Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study
Authors: Berengere Molina, Roberto Padoan, Maria Letizia Urban, Pavel Novikov, Marco Caminati, Camille Taillé, Antoine Néel, Laurence Bouillet, Paolo Fraticelli, Nicolas Schleinitz, Christine Christides, Laura Moi, Bertrand Godeau, Ann Knight, Jan Walter Schroeder, Sylvain Marchand-Adam, Helder Gil, Vincent Cottin, Cécile-Audrey Durel, Elena Gelain, Boris Lerais, Marc Ruivard, Matthieu Groh, Maxime Samson, Luca Moroni, Jens Thiel, Anna Kernder, Jan Willem Cohen Tervaert, Giulia Costanzo, Marco Folci, Sonia Rizzello, Pascal Cohen, Giacomo Emmi, Benjamin Terrier
Journal: Annals of the Rheumatic Diseases (2023)

Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA.We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3.Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab.These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.
Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis
Authors: Emely L. Verweyen, Kairavee Thakkar, Sanjeev Dhakal, Elizabeth Baker, Kashish Chetal, Daniel Schnell, Scott Canna, Alexei A. Grom, Nathan Salomonis, Grant S. Schulert
Journal: Journal of Clinical Investigation (2023)

Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.
Initial productive and latent HIV infections originate in vivo by infection of resting T cells
Authors: Stephen W Wietgrefe, Jodi Anderson, Lijie Duan, Peter J Southern, Paul Zuck, Guoxin Wu, Bonnie J Howell, Cavan Reilly, Eugène Kroon, Suthat Chottanapund, Supranee Buranapraditkun, Carlo Sacdalan, Nicha Tulmethakaan, Donn J Colby, Nitiya Chomchey, Peeriya Prueksakaew, Suteeraporn Pinyakorn, Rapee Trichavaroj, Julie L Mitchell, Lydie Trautmann, Denise Hsu, Sandhya Vasan, Sopark Manasnayakorn, Mark de Souza, Sodsai Tovanabutra, Alexandra Schuetz, Merlin L Robb, Nittaya Phanuphak, Jintanat Ananworanich, Timothy W Schacker, Ashley T Haase
Journal: Journal of Clinical Investigation (2023)

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.
Efficacy and safety of an inactivated virus-particle vaccine for SARS-CoV-2, BIV1-CovIran: randomised, placebo controlled, double blind, multicentre, phase 3 clinical trial
Authors: Minoo Mohraz, Katayoun Vahdat, Seyyed-Hadi Ghamari, Mohsen Abbasi-Kangevari, Erfan Ghasemi, Yasaman Ghabdian, Negar Rezaei, Maryam Amini Pouya, Asghar Abdoli, Mohammad-Reza Malekpour, Keyvan Koohgir, Sahar Saeedi Moghaddam, Payam Tabarsi, Mohsen Moghadami, Farzin Khorvash, Rozita Khodashahi, Mohammadreza Salehi, Hamed Hosseini
Journal: BMJ (2023)

Abstract Objective To report the efficacy, safety, and exploratory immunogenicity findings of two 5 µg doses of the BIV1-CovIran vaccine. Design Randomised, placebo controlled, double blind, multicentre, phase 3 clinical trial. Setting In six cities of Iran, including Bushehr, Isfahan, Karaj, Mashhad, Shiraz, and Tehran. The first vaccine or placebo injection of the first participant was on 16 May 2021 in Tehran. The last vaccine or placebo injection of the last participant occurred on 15 July 2021 in Isfahan. Participants 20 000 participants aged 18-75 years were randomly assigned to the intervention or placebo groups with a ratio of 2:1. Intervention 5 µg vaccine or placebo with the interval of 28 days. Main outcome measures Vaccine efficacy for a 90 day follow-up period, safety and explanatory immunogenicity assessment, and variant detection during the trial. Results 20 000 participants were recruited and randomly assigned to receive BIV1-CovIran (n=13 335 (66.7%)) or placebo (n=6665 (33.3%)). Participants' mean age was 38.3 (standard deviation 11.2) years, and 6913 (34.6%) were female. Among vaccinated participants that had covid-19 reported during the follow-up (median 83 days), 758 (5.9%) had symptoms, 144 (1.1%) had severe infection, and seven (0.1%) were critical. Among participants who received placebo during the follow-up, 688 (10.7%) had symptoms, 221 (3.4%) had severe infection, and 19 (0.3%) were critical. Overall efficacy was 50.2% (95% confidence interval 44.7% to 55.0%) against symptomatic covid-19, 70.5% (63.7% to 76.1%) against severe disease, and 83.1% (61.2% to 93.5%) against critical cases. Two deaths were reported in the efficacy population in the placebo group, no deaths were from the intervention group. During follow-up, 41 922 adverse events were reported: 28 782 (68.7%) were adverse reactions, of which 19 363 (67.3%) were in the intervention group. Most adverse reactions were mild or moderate in severity (grade 1 or 2) and self-limiting. No serious adverse events were related to the injections. For variant investigation, of 119 participants positive for the SARS-CoV-2 variant, 106 (89.1%) were positive for the delta variant. Conclusions A two dose regimen of the BIV1-CovIran vaccine conferred efficacy of 50.2% against symptomatic covid-19, 70.5% against severe disease, and 83.1% against critical disease. Vaccination was well tolerated, with no safety concerns raised. Trial registration Iranian Registry of Clinical Trials, IRCT20201202049567N3. Funding Shifa-Pharmed Industrial Group.
<i>The BMJ</i> ’s commitment to achieving net zero by 2040
Authors: Juliet Dobson, Sophie Cook, Kamran Abbasi
Journal: BMJ (2023)

The 2023 synthesis report from the Intergovernmental Panel on Climate Change leaves no doubt about the impact of human behaviour on planetary health and the urgent need to reduce greenhouse gas emissions. 1 The BMJ has long raised awareness about the climate emergency, highlighting the effects on people's physical and mental health and the consequences for biodiversity, wildlife, habitats, and the health of the planet.
The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells
Authors: Ning-Ning Liu, Cheng-Xiang Yi, Lu-Qi Wei, Jin-An Zhou, Tong Jiang, Cong-Cong Hu, Lu Wang, Yuan-Yuan Wang, Yun Zou, Yi-Kai Zhao, Le-Le Zhang, Ya-Ting Nie, Yi-Jing Zhu, Xin-Yao Yi, Ling-Bing Zeng, Jing-Quan Li, Xiao-Tian Huang, Hong-Bin Ji, Zisis Kozlakidis, Lin Zhong, Christopher Heeschen, Xiao-Qi Zheng, Changbin Chen, Peng Zhang, Hui Wang
Journal: Cancer Cell (2023)
Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
Authors: Thomas Kehrer, Anastasija Cupic, Chengjin Ye, Soner Yildiz, Mehdi Bouhaddou, Nicholas A. Crossland, Erika A. Barrall, Phillip Cohen, Anna Tseng, Tolga Çağatay, Raveen Rathnasinghe, Daniel Flores, Sonia Jangra, Fahmida Alam, Ignacio Mena, Sadaf Aslam, Anjali Saqi, Magdalena Rutkowska, Manisha R. Ummadi, Giuseppe Pisanelli, R. Blake Richardson, Ethan C. Veit, Jacqueline M. Fabius, Margaret Soucheray, Benjamin J. Polacco, Baran Ak, Arturo Marin, Matthew J. Evans, Danielle L. Swaney, Ana S. Gonzalez-Reiche, Emilia M. Sordillo, Harm van Bakel, Viviana Simon, Lorena Zuliani-Alvarez, Beatriz M.A. Fontoura, Brad R. Rosenberg, Nevan J. Krogan, Luis Martinez-Sobrido, Adolfo García-Sastre, Lisa Miorin
Journal: Cell Host & Microbe (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.